6-Substituted-1-methyl-1-H-benzimidazole derivatives are known to exert excellent insulin resistance improving activity, blood glucose lowering activity, anti-inflammatory action, immunomodulating activity, aldose reductase inhibitory activity, 5-lipoxygenase inhibitory activity, lipid peroxide production inhibitory activity, PPAR activating activity, anti-osteoporosis activity, leukotriene antagonizing activity, adipogenesis promoting effect, cancer cell proliferation inhibitory activity, calcium antagonizing activity, and the like. These 6-substituted-1-methyl-1-H-benzimidazole derivatives are known to be synthesized by condensation of 4-substituted-N2-methylbenzene-1,2-diamines in which an N-methylamino group is protected and corresponding carboxylic acid derivatives and followed by deprotection and intramolecular dehydration (for example, see Patent Literatures 1 and 2).
4-Substituted-N2-methylbenzene-1,2-diamines in which an N-methylamino group is protected can be synthesized from, for example, N-(5-substituted-2-nitrophenyl)-N-methylamines.
As a procedure for the preparation of N-(5-substituted-2-nitrophenyl)-N-methylamines, the preparation procedure by substituting a halogen atom of N-(5-halogeno-2-nitrophenyl)-N-methylamines with a nucleophilic reagent in the presence or absence of a base has been known (non patent literature 1). As a procedure for the preparation of the N-(5-halogeno-2-nitrophenyl)-N-methylamines used as the starting material in the above-mentioned preparation procedure, for example, the procedure for the preparation of N-(5-chloro-2-nitrophenyl)-N-methylamine by substituting a chlorine atom at the 2-position of 2,4-dichloronitrobenzene with methylamine has been known (patent literature 3). Since these N-(5-substituted-2-nitrophenyl)-N-methylamines are used as the manufacturing materials for the preparation of the 6-substituted-1-methyl-1-H-benzimidazole derivatives having high pharmaceutical activity, a preparation procedure for such N-(5-substituted-2-nitrophenyl)-N-methylamines, which is industrially more practical and additionally suitable for a large scale synthesis compared to the conventional procedure, has been desired to be developed.
Furthermore, as a procedure for the preparation of the 6-substituted-1-methyl-1-H-benzimidazole derivatives from the N-(5-substituted-2-nitrophenyl)-N-methylamines prepared by the above-mentioned reaction, the preparation procedure from N-(5-substituted-2-aminophenyl)-N-methylamines in which a methylamino group is protected, which can be prepared by reducing N-(5-substituted-2-nitrophenyl)-N-methylamines in which a methylamino group is protected previously, has been known (see patent literature 2), but a more efficient procedure for the preparation of the 6-substituted-1-methyl-1-H-benzimidazole derivatives by a shorter process has been desired to be developed.    [Patent Literature 1] Japanese Patent Publication (Kokai) Number Hei 9-295970    [Patent Literature 2] Japanese Patent Publication (Kokai) Number Hei 11-193276    [Patent Literature 3] European Patent Application No. 385850    [Non patent Literature 1] Journal of Medicinal Chemistry (USA) Vol. 39, p. 3971-3979 (1996)